PROJECT ABSTRACT RBC alloimmunization represents a major complication of chronic transfusion therapy. For those patients who are unfortunate enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time and resource intensive. Despite the clinical importance of alloantibodies, the molecular regulators of alloantibody production remain largely unknown. Patients with autoimmune diseases such as Systemic Lupus Erythematosus (SLE) have both higher rates of alloimmunization and aberrant T follicular helper cell (TFH) differentiation. Given the central role that TFH play in the generation of antibody responses, we are focused on understanding how SLE-associated pathways and downstream signaling events control TFH differentiation and alloimmunization responses in mice and humans. This proposal builds on the complementary expertise and recent findings from three different labs regarding the molecular control of TFH differentiation and function: (i) the Luckey lab and expertise with TFH differentiation in mouse models of alloimmunization, (ii) the Erickson lab with expertise with TFH differentiation in SLE mouse models and their regulation by the TNF family cytokine BAFF, and (iii) the Bender lab with expertise in TFH differentiation regulation by the transcription factor c-Myb. Our overarching hypothesis is that mice expressing SLE-associated genes will drive increased alloantibody generation in response to transfusion, and that BAFF signaling in T cells is a central driver of TFH differentiation and function in this setting. We subsequently hypothesize that BAFF signaling drives c-Myb expression, which in turn influences the accumulation of TFH and drives memory TFH formation. Finally, we hypothesize that both BAFF and c-Myb similarly control human TFH differentiation. By better understanding the molecular regulators of TFH differentiation and alloimmunization, we anticipate that in the fullness of time the results of these proposed studies will lead to the development of both clinically useful diagnostics and therapeutically druggable targets, ultimately helping to improve the lives of those chronically transfused patients who suffer most from the consequences of RBC alloimmunization.